Experimental and clinical data show that cocaine causes the appearance of markers of malignant ventricular arrhythmias and sudden death such as prolonged QT interval, decrease in heart rate variability, early afterdepolarizations and increase in QT interval dispersion. Our hypothesis is that cocaine's complex effects on the sympathetic nervous system, its effects on the parasympathetic nervous system, and its effects on cardiac potassium channels could result in the appearance of these markers. To test this hypothesis we will pursue the following specific aims: (l) identify the sites and mechanism(s) of action whereby cocaine activates sympathetic nervous system function; (2) determine the effect of cocaine on parasympathetic nervous system function, and identify the site(s) and mechanism(s) whereby cocaine exerts its effects; (3) further characterize the action of cocaine on potassium channels in cardiac tissue, and to clarify its effect primarily on the delayed rectifier potassium channel, since this is one of the ion channels that is extremely important for the repolarization of cardiac cells; and (4) identify the role of the sympathetic nervous system, the parasympathetic nervous system and the delayed rectifier potassium channel in the deleterious effects of cocaine on markers for sudden cardiac death, i.e., on heart rate variability and QT interval dispersion. For specific aim #4, each of these systems affected by cocaine (i.e., the 2 divisions of the autonomic nervous system and the potassium channel) will be teased out by utilizing dose-response curves, and pharmacological agents to block specific components of each system. Studies will be conducted in experimental animals wherein we will be addressing questions such as: Does cocaine act directly, independent of the CNS, on the adrenal medulla to release catecholamines? What is the role of cocaine's effect to inhibit peripheral norepinephrine uptake in its sympathomimetic effect? What is the effect of cocaine on spontaneous occurring cardiac parasympathetic nerve activity? What is the effect of cocaine on the delayed rectifier potassium channel? Answers to these questions will provide us with the basis to develop strategies to prevent cocaine-induced changes in autonomic nervous system function and potassium channel activity from increasing the incidence of sudden cardiac death.